6. Project Summary/Abstract Nearly a third of the world's population is infected with Mycobacterium tuberculosis (Mtb), resulting in 2 million deaths a year. After anti-TB drugs were developed starting in the 1940s, the incidence of TB in the US began to decline, only to resurge in the 1980s with the advent of HIV/AIDS. Today, the threat of Mtb evolving to become multi- or even extensively drug resistant (MDR/XDR-TB) poses global challenges to TB control. Recent reports of a patient with XDR-TB boarding an international flight is a stark reminder that TB does not respect borders. The busiest border crossing in the world (over 40,000 northbound crossings daily) loosely separates the >4 million residents of San Diego, CA, USA and Tijuana, BC, Mexico, which has the highest TB incidence in Mexico. After a 1997 survey found 41% of Tijuana's TB cases were resistant to at least one drug and 17% were resistant to isoniazid and rifampin (MDR-TB), universal drug susceptibility testing (DST) was recommended for all TB cases in Mexico, yet is rarely performed due to the cost. Consequently, the epidemiologic trajectory of TB in Mexico is unknown, but a high proportion of Mexican-born patients among San Diego's MDR-TB cases suggests that drug resistance in Tijuana has not declined. Increasing HIV incidence in Tijuana threatens to intensify the problem. The goal of this study is to describe the epidemiology of drug resistant TB in Tijuana in the context of HIV and the US/Mexican border. To achieve this goal, we propose DST and genotyping Mtb isolates from all newly diagnosed TB cases (n=1800- 2100) in Tijuana for over a 3-year period to address the following aims: 1) to measure the change in MDR-TB prevalence and determine the current XDR-TB prevalence;2) to determine whether primary MDR-TB transmission has increased relative to MDR-TB acquisition resulting from treatment failure and evaluate factors associated with MDR-TB;and 3) to characterize transmission dynamics and molecular relatedness of drug-sensitive and drug-resistant Mtb strains in Tijuana and California (where routine genotyping began in 2004), and describe the movement of unique strains from one side of the border to the other. Our aims are consistent with the USPHS's call for "renewed vigilance through drug-susceptibility testing, case reporting, specialty care, infection control, and expanded capacity." The proposed study will inform testing policy for MDR/XDR-TB in a developing country and highlight intervention targets for TB prevention in the US/Mexico border region. This study will not only provide key insights into prevalence and transmission of drug-resistant TB at a major US border, but produce an Mtb isolate repository for future studies and build capacity for improved TB control.